() is a foodborne pathogen capable of causing severe infections in newborns. The PhoP/PhoQ two-component system exerts a significant influence on bacterial virulence. This study aimed to investigate the impact of the PhoP/PhoQ system on intestinal inflammation in neonatal mice induced by . Neonatal mice were infected orally by BAA-894 (WT), a -gene-deletion strain (��), and a complementation strain (��), and the intestinal inflammation in the mice was monitored. Deletion of the gene reduced the viable count of in the ileum and alleviated intestinal tissue damage. Moreover, caspase-3 activity in the ileum of the WT- and ��-infected mice was significantly elevated compared to that of the �� and control groups. ELISA results showed elevated levels of TNF-�� and IL-6 in the ileum of the mice infected with WT and ��. In addition, deletion of the gene in resulted in a down-regulation of inflammatory genes (IL-1��, TNF-��, IL-6, NF-��B p65, TLR4) within the ileum and decreased inflammation by modulating the TLR4/NF-��B pathway. It is suggested that targeting the PhoP/PhoQ two-component system could be a potential strategy for mitigating -induced neonatal infections.